Compositions and method for regulating apoptosis
AssigneeThe Trustees of Princeton University
InventorYigong Shi
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Abstract
Peptides and peptidomimetics capable of modulating apoptosis through their interaction with cellular IAPs (inhibitor of apoptosis proteins) are disclosed. The peptides and mimetics are based on the N-terminal tetrapeptide of IAP-binding proteins, such as Smac/DIABLO, Hid, Grim and Reaper, which interact with a specific surface groove of IAP. Also disclosed are methods of using these peptides and peptidomimetics for therapeutic purposes and for rational drug design.
Claims32
A synthetic tetrapeptide that binds an Inhibitor of Apoptosis Protein (IAP) and relieves IAP-mediated inhibition of caspase activity, wherein the tetrapeptide binds a surface groove within a BIR domain of the IAP.
A compound that binds an Inhibitor of Apoptosis Protein (IAP) and relieves IAP-mediated inhibition of caspase activity, the compound having a formula R1-R2-R3-R4, wherein
- R1 is A or a mimetic of A;
- R2 is V, T or I, or a mimetic of V, T or I;
- R3 is P or A, or a mimetic of P or A;
- and
- R4 is F, Y, I or V, or a mimetic of F, Y, I or V.
A compound that binds an Inhibitor of Apoptosis Protein (IAP) and relieves IAP-mediated inhibition of caspase activity, the compound having a formula R1-R2-R3-R4-R5-R6-R7, wherein
- R1 is A or a mimetic of A;
- R2 is V, T or I, or a mimetic of V, T or I;
- R3 is P or A, or a mimetic of P or A;
- and
- R4 is F, Y, I or V, or a mimetic of F, Y, I or V;
- R5 is missing, or is Y or F, or a mimetic of Y or F;
- R6 is present only if R5 is present, and is L or I, or a mimetic of L or I;
- and
- R7 is present only if R5 and R6 are present, and is P or a mimetic of P.
A method of making a drug suitable for treating cell proliferative disease in a mammal by promoting apoptosis in proliferatively diseased cells, the method comprising:
- a) constructing a compound that binds a mammalian IAP and relieves IAP-mediated inhibition of caspase activity, wherein the compound binds a surface groove within a BIR3 domain of the IAP;
- and
- b) determining whether the compound promotes apoptosis in a proliferatively diseased cell, an affirmative determination indicating that the drug is suitable for treating the cell proliferative disease.
A method of screening for a compound that binds an IAP at a surface groove within a BIR domain, the method comprising:
- a) providing a synthetic tetrapeptide that binds a selected IAP and relieves IAP-mediated inhibition of caspase activity, wherein the tetrapeptide binds a surface groove within a BIR domain of the IAP;
- b) combining the tetrapeptide and the IAP in the presence of a test compound under conditions wherein, in the absence of the test compound, a pre-determined quantity of the tetrapeptide would bind the IAP;
- and
- c) determining if the quantity of the tetrapeptide bound to the IAP is decreased in the presence of the test compound, the decrease being indicative that the test compound binds the IAP and relieves IAP-mediated inhibition of caspase activity.
Dependencies are inferred from the claim text.